Functional Consequences of Age-Dependent Changes in Glutathione Status in the Brain

Significance: A decline in both cognitive and motor functions is one of the characteristics of aging. This results in changes in learning and memory, as well as deficits in balance and coordination that significantly impact the quality of life. Importantly, age is the greatest risk factor for a number of neurodegenerative diseases. Alterations in redox homeostasis, protein modification and processing, mitochondrial function, and the immune response have all been implicated in the decline of the aging brain. Recent Advances: Brain glutathione (GSH) decreases with age in humans, and a loss of GSH can impact cognitive function. Decreases in GSH are also associated with microglial activation and endothelial dysfunction, both of which can contribute to impairments in brain function. Changes in redox homeostasis can also potentiate the accumulation of advanced glycation endproducts, resulting in defects in protein processing and function as well as a further increase in inflammation. Critical Issues: We argue here that many of the changes in brain function associated with age are linked through GSH metabolism. Future Directions: Further research focused on better understanding how age affects GSH homeostasis with a particular emphasis on the key transcription factors involved in GSH metabolism is needed.